Immune-checkpoint blockade is a breakthrough in anticancer therapy, with dramatic sustained responses observed across a range of tumour types. Nevertheless, response rates are modest and acquired resistance can occur. IFNγ is a hallmark cytokine of an antitumour immune response, and disruption of the IFNγ pathway in tumour cells, particularly loss-of-function mutations in JAK1/JAK2, has been implicated in acquired resistance to programmed cell-death protein 1 blockade. A new study reveals that loss of IFNγ signalling might also underlie intrinsic resistance to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune-checkpoint inhibition.

Corresponding author Padmanee Sharma explains the rationale for this study: “we previously conducted a pre-surgical study with anti-CTLA-4 antibodies in patients with bladder cancer, and found that treatment with these antibodies increased the abundance of an ICOS+ T-cell subset that produced IFNγ. We hypothesized that tumour cells harbouring mutations in the IFNγ-signalling pathway would not be susceptible to the IFNγ produced by these T cells and, therefore, would be resistant to anti-CTLA-4 therapy.”

...non-responders had tumour tissues harbouring loss of IFNγ-pathway genes...

The researchers tested this hypothesis by evaluating genomic alterations of IFNγ-pathway genes in 16 patients with melanoma, four 'responders' and 12 'non-responders' to treatment with the anti-CTLA-4 antibody ipilimumab. “We found that non-responders had tumour tissues harbouring loss of IFNγ-pathway genes at significantly higher frequencies than observed in responders,” states Sharma. Indeed, 184 alterations (an average of 15.33) were detected in non-responders, compared with only four (one on average) in responders (P = 0.015).

Of note, although no significant enrichment of single-nucleotide variants was observed, 75% of non-responders had copy-number alterations (CNAs) versus 0% of responders (P = 0.019). These findings were validated in an independent cohort, using previously published data. The CNAs were mostly gene losses, particularly of IFNGR1, IRF1, JAK2, and IFNGR2, but some amplifications involving inhibitors of IFNγ signalling were also observed.

Using The Cancer Genome Atlas data, Sharma and co-workers found that patients with metastatic melanomas harbouring CNAs of IFNγ-pathway genes have shorter overall survival durations than those with tumours lacking such CNAs (40 months versus 48.2 months; P = 0.0018). This finding indicates that disruption of IFNγ signalling is associated with a poor prognosis, perhaps owing to reduced responsiveness of tumour cells to host antitumour immune responses.

“We plan to prospectively evaluate patients for responses to immune-checkpoint therapy based on the status of IFNγ-pathway genes in tumour tissues, and to determine whether combination therapy can effectively overcome the loss of IFNγ-pathway genes,” Sharma concludes.